Clinical implications of clopidogrel resistance.

The benefits of clopidogrel in the treatment and prevention of coronary artery disease are well established, however, not all individuals respond in the same way to clopidogrel; there are patients who suffer adverse events despite clopidogrel treatment. This review focuses on the definition, potential mechanisms for and clinical implications of clopidogrel resistance, as well as the strategies to improve the response to this antiplatelet drug. There is an inter-individual variability in response to clopidogrel therapy, and a sub-optimal response (clopidogrel resistance) has been associated with adverse cardiovascular events. Nevertheless, there is no clear and consensual definition of clopidogrel resistance. Response to clopidogrel therapy follows a normal, bell-shaped distribution, so a more appropriate description would be variable response rather than clopidogrel resistance. Independent of the term used, lower response to clopidogrel therapy seems to be associated with a higher probability of suffering thrombotic events. Due to the misleading definition of resistance and non-standardized method for assessing platelet inhibition, current guidelines do not recommend the use of platelet function assays to monitor the inhibitory effect of antiplatelet drugs. Current guidelines also do not recommend clopidogrel loading doses higher than 300 mg and daily maintenance doses higher than 75 mg, even though a regimen of 600 mg clopidogrel loading dose seems to be preferred for patients undergoing percutaneous coronary interventions.

Association between level of platelet inhibition after early use of abciximab and myocardial reperfusion in ST-elevation acute myocardial Infarction treated by primary percutaneous coronary intervention.

The interindividual response to antiplatelet treatment is considerable, with the magnitude of response often related to the appearance of clinical events after elective percutaneous coronary intervention (PCI). We investigated whether platelet aggregation inhibition (PAI) by early administration of abciximab would affect myocardial reperfusion outcomes observed after PCI in patients with acute ST-elevation myocardial infarction (STEMI). Consecutive patients with STEMI who were treated with PCI in our center were recruited (n = 56). Successful reperfusion was defined as a final Thrombolysis In Myocardial Infarction grade 3 flow, myocardial blush grade 2 or 3, and ST-segment resolution >50%. PAI grade was determined with the Ultegra Rapid Platelet Function Assay. Successful reperfusion criteria were observed in 34 patients (61%). There were 6 patients (11%) with a PAI value <80% and 34 (61%) with a PAI value > or =95%. Eight patients (36%) of those whose PAI was <95% had all the indicators of successful reperfusion compared with 26 patients (77%) whose PAI was > or =95% (p = 0.005). After adjusting for other variables (time from symptom onset to balloon, which was independently associated with myocardial reperfusion), the relation remained significant (p = 0.006). In conclusion, in patients with STEMI that was treated with direct PCI, higher platelet inhibition responses with early administration of abciximab were associated with better myocardial reperfusion outcomes.

A randomized comparison of novel bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with acute coronary syndromes: The CENTURY II high risk ACS substudy.

BACKGROUND: To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial. METHODS: CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24months. RESULTS: The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P=0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P=0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate. CONCLUSIONS: BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up.

Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction).

OBJECTIVES: The goal of this trial was to study the long-term effects of intravenous (IV) metoprolol administration before reperfusion on left ventricular (LV) function and clinical events. BACKGROUND: Early IV metoprolol during ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size when used in conjunction with primary percutaneous coronary intervention (pPCI). METHODS: The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial recruited 270 patients with Killip class ≤II anterior STEMI presenting early after symptom onset (<6 h) and randomized them to pre-reperfusion IV metoprolol or control group. Long-term magnetic resonance imaging (MRI) was performed on 202 patients (101 per group) 6 months after STEMI. Patients had a minimal 12-month clinical follow-up. RESULTS: Left ventricular ejection fraction (LVEF) at the 6 months MRI was higher after IV metoprolol (48.7 ± 9.9% vs. 45.0 ± 11.7% in control subjects; adjusted treatment effect 3.49%; 95% confidence interval [CI]: 0.44% to 6.55%; p = 0.025). The occurrence of severely depressed LVEF (≤35%) at 6 months was significantly lower in patients treated with IV metoprolol (11% vs. 27%, p = 0.006). The proportion of patients fulfilling Class I indications for an implantable cardioverter-defibrillator (ICD) was significantly lower in the IV metoprolol group (7% vs. 20%, p = 0.012). At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046). CONCLUSIONS: In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions. (Effect of METOprolol in CARDioproteCtioN During an Acute Myocardial InfarCtion. The METOCARD-CNIC Trial; NCT01311700).

P2Y12 platelet reactivity after thrombolytic therapy for ST-segment elevation myocardial infarction.

INTRODUCTION: Thrombolysis, as reperfusion therapy for ST segment elevation myocardial infarction (STEMI), induces a pro-thrombotic status with enhanced platelet activity; this study aims to evaluate P2Y12 platelet reactivity and response to clopidogrel in the post-thrombolysis scenario. MATERIALS AND METHODS: Observational, prospective study, including consecutive patients with elective angiography after thrombolytic therapy for STEMI. Every patient received antiplatelet therapy with loading doses of 250 mg aspirin and 300 mg clopidogrel on admission followed by 100mg aspirin and 75 mg clopidogrel daily. P2Y12-dependent platelet reactivity (expressed in P2Y12-Reaction Units, PRU) was assessed with VerifyNow® device on admission, daily after thrombolysis and pre-angiography. RESULTS: 41 patients fulfilled the inclusion criteria. Median time between thrombolysis and angiography was 2,5 days (IQR 1,8-4,1). Post-treatment platelet reactivity (PPR) showed poor correlation with time on clopidogrel treatment (r2=0.04) and reached a maximum value of 274 ± 84 PRU during the first 24h after thrombolysis (Day +1 determination). After this, values showed a progressive reduction until the point of angiography (249 ± 82 PRU), without significant differences between consecutive time-points (p=0,549). Inhibition of platelet aggregation (IPA) assessed as a percentage of P2Y12 receptor blockage was poor, increasing gradually from 0 ± 4% on admission to 11 ± 6% the day of the angiography (p=0,001). 71,4% of patients showed PPR ≥ 208 PRU during angiography. CONCLUSIONS: Platelet reactivity, as assessed by post-treatment P2Y12 mediated reactivity, is heightened after thrombolytic therapy during STEMI management. In this scenario, standard doses of clopidogrel did not achieve significant inhibition of ADP-mediated platelet reactivity.

Vasomotor response to different endothelium-dependent vasodilators in an animal model.

BACKGROUND AND OBJECTIVES: Incomplete re-endothelialization of stents can be revealed as paradoxical vasoconstriction with endothelium-dependent vasodilators. As no consensus exists about the best method or agent, our objective is to analyze the response to different drugs in a coronary swine model. METHODS: Twenty-seven stents were implanted in 9 domestic swine. The vessel diameter of proximal and distal segments (≥5 mm) was assessed immediately post implantation. Different endothelium-dependent vasodilators were used: intracoronary (IC) acetylcholine, 20 µg (A2) and 40 µg (A4), IC serotonin (S), 100 µg, and isoproterenol (I), intravenous infusion. The results are presented as constriction (%) compared with maximal vasodilation with IC nitroglycerin (N, 200 µg). RESULTS: In 10 vessels (37%), A4 provoked an occlusive spasm. Acetylcholine induced a higher degree of vasoconstriction (A4, 42 ± 39%; A2, 16 ± 14%) than the rest of the agonists (S, 6 ± 12%; I, 6 ± 11%; P<.01). The constriction rate was not related to the induced hemodynamic changes. CONCLUSIONS: After focal endothelial denudation in a coronary swine model, the constriction rate induced by different endothelium-dependent vasodilators is highly variable. The highest value is observed after IC acetylcholine bolus. The constriction rate does not correlate with the observed hemodynamic changes.

Mitral valve prosthesis implanted in atrial wall over huge calcified annulus.

We describe an alternative technique for mitral valve replacement in patients with severe mitral annular calcification, in whom conventional techniques are not feasible. A new annulus that allows supra-annular prosthetic implantation is created.

[Instent restenosis related to vessel injury score degree. Are current experimental models valid for drug-eluting stents analysis?]. / La reestenosis en el stent depende del daño vascular inducido. ¿Son válidos los modelos experimentales actuales de análisis de los stents farmacoactivos?

INTRODUCTION AND OBJECTIVES: Drug-eluting stents are useful for preventing restenosis, but the patho-physiological processes involved in the proliferative response after implantation are still not known in detail. The aim of this study is to compare the coronary vascular histomorphometry after implanting drug-eluting stents and bare metal stents in a swine model. METHODS: Sixty stents were randomly implanted in 20 Large White female pigs with a ratio of baremetal/drug-eluting stents of 1:2. After 28 days, euthanasia and histomorphometry were performed. We defined the vessel injury score in accordance to whether the internal elastic lamina was intact or ruptured. RESULTS: There were no differences between drug-eluting stents and bare metal stents in the intact internal elastic lamina group regarding neointimal area or % restenosis (1.3 [1.1-2.2]) vs 2.0 [1.3-2.5] mm²; P=.6; and 14.0 [12.1-20.8] vs 22.2 [14.1-23.3] %; P=.5). We assessed statistically significant differences for the ruptured internal elastic lamina group, (neointimal area 1.2 [0.8-2.0] vs 2.9 [2.3-3.7] mm²; P=.001 and % restenosis 16.63 [11.2-23.5] vs 30.4 [26.4-45.7] %; P=.001). CONCLUSIONS: In our swine model, we did not find any differences between proliferative response of drug-eluting stents and bare metal stents when the internal elastic lamina is intact; differences are only found when vascular injury is deeper.

Giant left main coronary artery to right atrium fistula.

Aneurysmal arterial origin of coronary fistulae is an extremely rare combination. We report a case of a giant left main coronary artery to right atrium fistula in a 48-year-old male. We describe the clinical course and management options.

Influence of platelet reactivity and response to clopidogrel on myocardial damage following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndrome.

INTRODUCTION: A wide variability in the response to clopidogrel and magnitude of post-treatment platelet reactivity has been described. However, this has been demonstrated by light transmittance aggregometry, a method too laborious for daily practice. Point-of-care devices may overcome this limitation, but little is known on the predictive value of such measurements. Our objective was to determine the relationship between platelet reactivity and the incidence of myocardial damage following percutaneous coronary intervention (PCI) in patients with Non-ST-segment Elevation Acute Coronary Syndrome (NSTEACS). MATERIALS AND METHODS: This prospective study included 93 patients with NSTEACS and PCI. All patients received a loading dose of 300 mg of clopidogrel and 250 mg of aspirin. Myocardial damage was defined as any elevation above upper limit of normal or previous levels of troponin T, assessed every 6 h for at least 24 h following PCI. Platelet reactivity not related to clopidogrel (BASE reactivity), related to P2Y12 inhibition (P2Y12 reactivity) and inhibition of platelet aggregation (IPA) were assessed immediately pre-PCI with the VerifyNow device. RESULTS: Myocardial damage was detected in 60 patients (64.5%). Higher BASE reactivity was associated with myocardial damage (287.8+/-62.6 vs. 260+/-55.9 units, p=0.043) while a trend was found for P2Y12 reactivity (173.4+/-70.3 vs. 149.2+/-58.4 units, p=0.109). No relationship was detected for IPA. Multivariate logistic regression analysis confirmed that BASE reactivity (p=0.04) and P2Y12 reactivity (p=0.03) were independent predictors of myocardial damage. CONCLUSIONS: Platelet reactivity before PCI appears to be better predictor of myocardial damage than does response to clopidogrel.